Abstract In patients under suppressive antiretroviral therapy (ART), HIV-1 persists in a latent state primarily in resting CD4+ T cells. Both neutralizing and non-neutralizing antibodies (nNAbs) targeting HIV-1 envelop protein can mediate killing of infected cells through antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells or antibody-dependent cellular phagocytosis (ADCP) by macrophages and other phagocytes. Since ART does not directly kill HIV-1-infected cells, antibodies can play an important role in elimination of the residual viral reservoirs. Broadly reactive neutralizing antibodies (bNAbs) that could neutralize a wide spectrum of clinical HIV- 1 isolates brought new hope to HIV cure research. There is burgeoning evidence that the Fc fragment is important to the antibody-mediated viral suppression. Moreover, the Fc fragment is indispensable for antibody- mediated cell killing because of its engagement with Fc-receptors (FcR) on the innate effector cells. It is important to evaluate antibody efficacy in tissues, especially in lymphoid tissues, because they are the major sites for HIV- 1 infection and are the most important anatomical reservoirs for HIV-1. The cell-killing functions of tissue innate effector cells are critical to antibody therapeutic effects. We compared NK cells from human tonsils or lymph nodes with those from peripheral blood, and found that vast majority of the NK cells in lymphoid tissues are immature and deficient in ADCC activity because:1) they do not express Fc-gamma receptor IIIA (CD16a); 2) they produce very little cytolytic molecules such as granzyme B and perforin. The objective of this grant is to study how to improve Fc-dependent effector cell functions to clear HIV-1 reservoirs using human tissue biopsies and humanized mouse models. We aim to: 1) develop the novel approaches to enhance ADCP activity; 2) improve maturation of NK cells in lymphoid tissues to acquire ADCC activity. Our study will provide critical implications to antibody-based HIV cure research.